DESCRIPTION: (Adapted from the applicant's description): The immediate goals of the PI are to expand the focus of his research from familial forms of polycystic ovary syndrome (PCOS), and genetic influences on the development of the syndrome into areas with even greater clinical impact. Specifically the goals of this application are to 1) identify other unrecognized morbidity that results from insulin resistance in PCOS and in the long term. 2) expand the clinical trials of improving insulin sensitivity as a primary treatment modality in PCOS. Another long-term goal is to develop within the medical center a cadre of investigators interested in PCOS patient-oriented research. The overall hypothesis of this proposal is that insulin resistance is the fundamental pathophysiologic defect in women with PCOS, that its effects can be protean and unrecognized, and that metabolic abnormalities worsen with age. Our preliminary studies suggest that insulin resistance is major contributor to both the etiology of PCOS and its association with sleep apnea. We propose further studies to clarify the role of insulin resistance in both PCOS and control female populations on sleep disorders. We theorize that there is enhanced steroidogenesis in endometrial glandular and stromal cells from women with PCOS and this is further stimulated by hyperinsulinemia. We intend to study these hypotheses in endometrial tissue form PCOS women and appropriate controls. Our preliminary experience suggests that insulin resistance over time will lead to a worsening of glucose tolerance and other metabolic markers in PCOS women with an improvement in reproductive abnormalities such as anovulation and hyperandrogenemia. We propose to identify clinical interventions in PCOS women that will improve insulin sensitivity and manifestations of the syndrome. Improving insulin action through diet and exercise, with and without weight loss, will result in lowered circulating insulin levels, lowered androgens and increased ovulatory frequency rate in PCOS women.